EP0495769A2 - Réacteur pour la mise en oeuvre des réactions biologiques utilisant biocatalyseurs - Google Patents

Réacteur pour la mise en oeuvre des réactions biologiques utilisant biocatalyseurs Download PDF

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Publication number
EP0495769A2
EP0495769A2 EP92890009A EP92890009A EP0495769A2 EP 0495769 A2 EP0495769 A2 EP 0495769A2 EP 92890009 A EP92890009 A EP 92890009A EP 92890009 A EP92890009 A EP 92890009A EP 0495769 A2 EP0495769 A2 EP 0495769A2
Authority
EP
European Patent Office
Prior art keywords
reactor
stirring device
reactor according
designed
circulation line
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP92890009A
Other languages
German (de)
English (en)
Other versions
EP0495769B1 (fr
EP0495769A3 (en
Inventor
Hermann W.D. Dipl.-Ing. Dr. Katinger
Manfred Dipl.-Ing. Dr. Reiter
Gerald Dipl.-Ing. Blüml
Nicolaus Zach
Theodor Gaida
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vogelbusch GmbH
Original Assignee
Vogelbusch GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vogelbusch GmbH filed Critical Vogelbusch GmbH
Publication of EP0495769A2 publication Critical patent/EP0495769A2/fr
Publication of EP0495769A3 publication Critical patent/EP0495769A3/de
Application granted granted Critical
Publication of EP0495769B1 publication Critical patent/EP0495769B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/24—Gas permeable parts
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/34—Internal compartments or partitions
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/14—Scaffolds; Matrices
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/16—Particles; Beads; Granular material; Encapsulation
    • C12M25/18—Fixed or packed bed
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/813—Continuous fermentation

Definitions

  • the invention relates to a reactor for carrying out biological reactions by means of biocatalysts with a base part, in which a stirring device and monitoring and control organs or devices are arranged, and a cover which can be placed tightly.
  • Reactors are also already known in which the biocatalysts are immobilized on a carrier matrix, for example so-called "microcarriers", or the biocatalysts themselves form their own matrix by agglomeration.
  • the microcarrier or the biocatalyst matrix is arranged in a cylinder, through which substrate flows from below, to such an extent that the microcarrier or the biocatalyst matrix are fluidized in the form of a fluidized bed. Substrate flows through this matrix or the microcarrier, but remains in the cylinder due to its specific weight and the coordinated flow velocity, whereas the converted substrate is drawn off at the upper end and circulated.
  • the circulation line is fed to a gas exchanger in which the substrate is enriched with oxygen and the carbon dioxide formed is drawn off. Furthermore, heating elements, pH measuring elements, oxygen probes, temperature probes and a circulation pump are then arranged in the circulation line.
  • Such designs have the disadvantage that only as much oxygen can be introduced into the substrate as is dissolved therein, so that a drop in the oxygen concentration takes place within the fluidized bed to such an extent that the oxygen content of the substrate in the upper region of the fluidized bed is so low that further reaction is hindered.
  • the invention has for its object to provide a reactor of the type mentioned, with which the biocatalysts a sufficient supply of the gas required for the reaction is available over the entire length.
  • this object is achieved in that an intermediate part is inserted between the base part and the lid, which, when used as a fluidized bed reactor and / or fixed bed reactor, has in its lower region a gas-bubble-permeable carrier, in particular a carrier plate, for a matrix or biocatalyst matrix loaded with biocatalysts , wherein a circulation line leading from the upper region of the intermediate part to the base part is provided, and wherein the stirring device is designed as a circulation pump.
  • the design according to the invention converts a conventional reactor into a fluidized bed reactor or fixed bed reactor, as a result of which the monitoring and control devices or devices available for a conventional reactor can also be used in the fluidized bed reactor.
  • the intermediate part can advantageously be modularly interchangeable, so that the expensive equipment of the base part can be used for a large number of reactor types.
  • the carrier formed by the carrier plate can have a hydrophobic surface and a permeability of 3 to 12%, preferably 5 to 7.5%. It is thereby achieved that air bubbles can pass through the carrier plate unhindered without forming large bubbles on the underside, which then pass through the carrier plate in an eruption-like manner and the matrix loaded with biocatalysts or drag the biocatalyst matrix upwards.
  • the gas-bubble-permeable support can be designed as a static mixer, as a result of which the reactor liquid is mixed again intensively with the gas.
  • the circulation line can be designed as a central tube, optionally closed by a grid, which passes through the carrier plate and leads to the stirring device. This prevents energy losses through an external tube, and apart from the smaller space requirement, the device according to the invention is particularly easy to sterilize and clean.
  • the central tube forming the circulation line can be provided at its lower region with a collar which overlaps the outside of the impeller of the stirring device forming the pump, the stirring device being designed as an axial conveyor. A particularly good circulation is thereby achieved, with a uniform circulation being achieved by the central withdrawal of the liquid.
  • the wing of the stirring device can be arranged approximately in the longitudinal center of the collar.
  • baffles can be used to prevent the reactor liquid from rotating, as a result of which the liquid strikes the support plate in a substantially vertical direction from below and therefore flows uniformly from bottom to top, so that uniform flow conditions in the fluidized bed or Fixed bed are reached.
  • the wall of the circulation line can be designed at least in partial areas thereof as a filter membrane, e.g. ultrafilter membrane, or as a permeation membrane.
  • gas introduction elements can be placed in the circulation line above the stirring device, in particular in the extended transition area be provided.
  • the introduced gas is immediately finely distributed in the liquid by the stirring device and then introduced as finely divided bubbles through the carrier plate into the fixed bed or fluidized bed.
  • the impeller of the stirring device can be designed with low shear force, so that even cells in suspension survive and can be returned to the matrix without lysis products occurring, e.g. are due to the mechanical damage to the cells by the stirring device.
  • the stirring device can be driven so that it can be reversed in the direction of rotation, as a result of which the fluidized bed or the fixed bed is firmly packed, or a good inoculation of the fluidized bed or fixed bed can be achieved in this way by backwashing.
  • the reactor consists of a base part 1, a cover 2 and an intermediate part 3 arranged therebetween.
  • the intermediate part 3 can be exchanged in a modular manner, in the present case the intermediate part being designed for a fluidized bed reactor or fixed bed reactor.
  • the intermediate part 3 has in its lower region a porous carrier plate 4, which is formed from hydrophobic material and has a permeability of 3 to 12%, in the present case 5 to 7.5%.
  • the carrier plate is effective due to its design as a static mixer and gas bubble permeable due to the hydrophobic surface and the stated permeability.
  • a central circulation line 5 is provided in the intermediate part 3 and is provided with an inlet funnel 6 at its upper end.
  • the inlet funnels 6 are indicated at three different heights, these inlet funnels being attached depending on the filling level of the reactor.
  • the upper side of the inlet funnels is covered by a grid 7, on the one hand to prevent the formation of a vortex when sucking in and on the other hand also the filling material to prevent the fixed bed or fluidized bed from sucking into the circulation line.
  • the filler material is indicated at 8.
  • the filling material 8 can either be a carrier matrix for biocatalysts, so-called “microcarriers”, which have a specific weight and have a correspondingly porous structure, so that the biocatalysts, e.g. Microorganisms, cells from cell cultures, enzyme chains and the like, to which microcarriers can adhere, or the microcarriers are interspersed with the organisms.
  • the reactor can also be designed such that the biocatalysts used are so-called suspension cells, i.e. Cells that only adhere to the surface of the microcarrier due to mechanical interaction.
  • the central circulation line continues with an extension 5 'in the base part 1 and is connected at its lower end to a flared transition part 9.
  • This transition part connects the circulation line with a cylindrical collar 10, in which the impeller 11 of a stirring device 12 is arranged.
  • the agitator blade 11 forms an axial pump together with the collar and can be driven in both conveying directions by means of an electric motor 13 which can be reversed in the direction of rotation.
  • Baffles 14 are arranged in the interior of the conical transition part 9, which prevent the liquid from rotating within the cylindrical collar 10.
  • baffles 15 are also provided, by means of which the liquid emerging from the cylindrical collar below is deflected so that it flows vertically upwards and thus passes uniformly through the porous carrier plate 4.
  • a gas introduction line 16 opens into the transition part 9, by means of which gas is introduced in a finely divided manner into the liquid flow leading to the impeller. The gas is then broken up even more by the impeller, and it then enters the reactor with the liquid at the lower end of the cylindrical collar 10 and flows with the liquid up to the porous support plate, where, owing to the hydrophobic formation of the Carrier plate 4 can pass the gas bubbles without adhering to the carrier plate and thus the fluidized bed or roam the fixed bed. During this roaming, new gas exchange surfaces are created due to the friction of the gas bubbles on the filling bodies 8, as a result of which an increased gas / liquid mass transfer is achieved. For example, there will always be a sufficient amount of oxygen available up to the top of the reactor.
  • With 17 is a connection piece for sample-drawing devices, measuring electrodes such as oxygen electrode, pH electrode and the like. designated. Samples can also be taken from the sampling device 18 or from a reserve nozzle 19, which can also be used for introducing gas.
  • the stirring blade 11 of the stirring device 12 is designed with low shear force, i.e. on the one hand there are no sharp striking edges which can damage the cells, and on the other hand the geometry of the pump vane is designed in such a way that the delivery capacity is maximized and at the same time turbulent and mechanical shear effects are minimized.
  • Process example 1 (adherent cell type); Culture in the fluid bed reactor:
  • Process example 1 illustrates the culture of an adherent animal cell line, an IgG secreting, recombinant CHO cell (source IAM) as a typical case of a cell line which uses the growth and maintenance of the metabolic activity preferably anchored to a carrier matrix.
  • source IAM IgG secreting, recombinant CHO cell
  • the recombinant CHO cells were cultivated in the present process example 1 with DMEM / HAM's F 12 medium with 5% fetal calf serum under standard conditions (37 ° C., pH 7.1) in a 10 liter laboratory fluidized bed reactor on porous microcarriers.
  • the cell densities achieved over a period of 970 hours are shown in FIG.
  • the maximum cell density achieved was 140 x 106 cells per milliliter porous carrier matrix.
  • the arrow inserted at test hour 466 indicates the use of protein-free culture medium, as a result of which there was only little impairment of growth and metabolism.
  • This example is representative of many standard cell lines such as recombinant and non-recombinant CHO, BHK, VERO etc.
  • Process example 2 type of a suspension cell
  • Culture in the fluid bed reactor
  • Process example 2 shows the culture of a suspension cell line, a mouse / human hybrid (source IAM).
  • source IAM mouse / human hybrid
  • the suspension cells were cultivated with RPMI 1640 medium, mixed with 2% fetal calf serum, under standard conditions (37 ° C., pH 6.95) in a 10 liter laboratory fluid bed reactor on porous microcarriers.
  • the cell densities achieved over a period of 2000 hours are shown in FIG. 3.
  • the maximum cell density achieved was 4.5 ⁇ 10il cells per milliliter of porous carrier matrix. This is an increase by a factor of 10 to 15 compared to the cell densities achieved in conventional reactor types (chemostatic culture).
  • Process example 2 allows the conclusion that even very slowly and in low density growing hybridoma cells (human hybrids, xenohybrids) with the described fluidized bed reactor system in high cell densities, i.e. in cell densities well above 106 hybrids per milliliter, are to be cultivated.
  • Process example 3 shows the culture of a suspension cell line, (mouse x mouse hybridoma cell line).
  • the suspension cells were mixed with RPMI 1640 medium under standard conditions (37 ° C., pH 7) 10 liter laboratory fluid bed reactor cultivated on porous microcarriers.
  • the cell densities achieved over a test period of 2000 hours are shown in FIG.
  • the maximum cell density achieved was 8 x 106 cells per milliliter of porous carrier matrix.
  • the arrows between trial hours 400 and 1600 indicate the use of serum-free perfusion media. It can be seen from the illustration that even when serum-free media are used, the culture has normal growth and unchanged metabolic activity over large areas.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Sustainable Development (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Clinical Laboratory Science (AREA)
  • Immunology (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
EP92890009A 1991-01-16 1992-01-15 Réacteur pour la mise en oeuvre des réactions biologiques utilisant biocatalyseurs Expired - Lifetime EP0495769B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AT0009391A AT394576B (de) 1991-01-16 1991-01-16 Reaktor zur durchfuehrung biologischer reaktionen mittels biokatalysatoren
AT93/91 1991-01-16

Publications (3)

Publication Number Publication Date
EP0495769A2 true EP0495769A2 (fr) 1992-07-22
EP0495769A3 EP0495769A3 (en) 1992-11-19
EP0495769B1 EP0495769B1 (fr) 1995-09-13

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ID=3481327

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EP92890009A Expired - Lifetime EP0495769B1 (fr) 1991-01-16 1992-01-15 Réacteur pour la mise en oeuvre des réactions biologiques utilisant biocatalyseurs

Country Status (7)

Country Link
US (1) US5246855A (fr)
EP (1) EP0495769B1 (fr)
JP (1) JP3171634B2 (fr)
AT (1) AT394576B (fr)
CA (1) CA2059367C (fr)
DE (1) DE59203610D1 (fr)
DK (1) DK0495769T3 (fr)

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US20050032211A1 (en) * 1996-09-26 2005-02-10 Metabogal Ltd. Cell/tissue culturing device, system and method
IL155588A0 (en) * 2003-04-27 2003-11-23 Metabogal Ltd Methods for expression of enzymatically active recombinant lysosomal enzymes in transgenic plant root cells and vectors used thereby
AU5384598A (en) * 1996-12-31 1998-07-31 Rorer Pharmaceutical Products Inc. Method and apparatus for selective depletion of biological particles
US20030100945A1 (en) 2001-11-23 2003-05-29 Mindguard Ltd. Implantable intraluminal device and method of using same in treating aneurysms
CA2353307A1 (fr) 2001-07-13 2003-01-13 Carmen Parent Appareil et procede pour le traitement des effluents gazeux
US7951557B2 (en) 2003-04-27 2011-05-31 Protalix Ltd. Human lysosomal proteins from plant cell culture
JP2007522801A (ja) 2004-01-07 2007-08-16 リーブテック，インコーポレイテッド 一体のスパージャーとセンサー受け器を有する混合用袋
BE1016793A4 (fr) 2005-10-04 2007-06-05 Artelis Procede de culture de cellules et dispositif permettant sa mise en oeuvre.
EP2150608B1 (fr) 2007-05-07 2017-11-29 Protalix Ltd. Bioréacteur jetable à grande échelle
WO2016061526A1 (fr) 2014-10-17 2016-04-21 Sani-Tech West, Inc. Système et procédé de mélange et de filtration
EP3034159B1 (fr) * 2014-12-18 2020-11-04 The Procter and Gamble Company Mélangeur statique et procédé pour mélanger des fluides
US10729600B2 (en) 2015-06-30 2020-08-04 The Procter & Gamble Company Absorbent structure
WO2017079597A1 (fr) 2015-11-04 2017-05-11 The Procter & Gamble Company Structure absorbante
HUE057989T2 (hu) 2015-11-04 2022-06-28 Procter & Gamble Nedvszívó szerkezetet tartalmazó nedvszívó árucikk
EP3370673B1 (fr) 2015-11-04 2022-03-30 The Procter & Gamble Company Structure absorbante
US20230017014A1 (en) * 2019-12-02 2023-01-19 Univercells Technologies S.A. Bioreactor with enhanced gas transfer and thermal regulation
WO2021110767A1 (fr) * 2019-12-02 2021-06-10 Univercells Technologies S.A. Bioréacteur à transfert de gaz et régulation thermique améliorés

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Also Published As

Publication number Publication date
CA2059367A1 (fr) 1992-07-17
JPH0584063A (ja) 1993-04-06
DE59203610D1 (de) 1995-10-19
US5246855A (en) 1993-09-21
EP0495769B1 (fr) 1995-09-13
JP3171634B2 (ja) 2001-05-28
EP0495769A3 (en) 1992-11-19
AT394576B (de) 1992-05-11
DK0495769T3 (da) 1996-02-05
CA2059367C (fr) 2002-05-28
ATA9391A (de) 1991-10-15

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